IKZF2 (Helios) and IKZF4 (Eos)

Class

CELMoD (cereblon E3 ligase modulator); molecular degrader

Pathway

Cereblon-mediated ubiquitination and proteasomal degradation of IKZF2/IKZF4 in regulatory T cells

IKZF2 (Helios) and IKZF4 (Eos) are zinc-finger transcription factors that help regulatory T cells (Tregs) maintain a stable, immunosuppressive identity. Tregs normally restrain immune responses to prevent autoimmunity, but within tumors this same suppressive activity can shield cancer cells from immune attack. Molecules called CELMoDs (cereblon E3 ligase modulators) work by binding cereblon, a component of a cellular protein-disposal machine, and redirecting it to grab hold of IKZF2 and IKZF4 so they are tagged for destruction by the proteasome. Removing these transcription factors destabilizes Tregs, reducing their suppressive function and potentially allowing effector T cells and other immune cells to mount a stronger response against tumor cells. Targeting both Helios and Eos together, rather than either alone, is intended to achieve more thorough disruption of Treg stability, since the two factors have overlapping roles. This mechanism is being explored mainly in oncology, particularly for cancers that evade immune surveillance through Treg-mediated suppression, and more broadly reflects growing interest in using targeted protein degradation to modulate transcription factors that were previously considered difficult to drug with conventional inhibitors.